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Tamer Elhabibi

Chapter Seven

Bioavailability and bioequivalence

Definitions
Bioavailability: measurement of the rate and extent to which the active moiety becomes
available at the site of action. It is also the rate and extent of active drug that is systemically
absorbed.
Bioequivalent drug products: a generic drug product is considered bioequivalent to the
reference brand drug product if both products are pharmaceutical equivalents and have
statistically the same bioavailability for the same dose, in the same chemical form, similar
dosage form, by same route of administration, under same experimental conditions.
Generics: requires abbreviated NDA for FDA approval after patent expiration. Must be a
therapeutic equivalent but may differ in shape, scoring, packaging, excipients, expiration
dates, labeling.
Pharmaceutical equivalents: drug product that contain the same active drug, same salt, ester
or chemical form, same dosage form, identical in strength and route of administration. May
differ in release mechanism, shape, scoring, packaging, excipients.
Reference drug product: usually the currently marketed brand name with full NDA and
patent protection.
Therapeutic equivalent drug products: are pharmaceutical equivalents that can be expected
to have the same clinical effect and safety profile under same conditions.
Pharmaceutical alternatives: are drug products that contain the same therapeutic moiety but
are different salts, ester or complexes or are different strength or dosage forms (tablet vs cap,
instant release vs SR).

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Bioavailability and bioequivalence

Acute pharmacologic effect

Examples: change in heart rate, blood pressure, ECG, clotting time, Forced Expiratory Volume
(FEV1). Alternative to plasma concentration when that is not possible or inappropriate.
Measure effect vs. time. Onset time: time from drug administration till achieving the
minimum effective concentration (MEC) at the receptor site as evidenced by pharmacological
response. Intensity: proportional to the # of receptors occupied by the drug up to a maximum
pharmacological effect, which may occur before, at or after peak drug absorption. Duration
of action: time for which the drug concentration remains above MEC. Therapeutic window:
concentration between the MEC and minimum toxic concentration (MTC). As concentration ↑
 other receptor interactions lead to SE. In vitro test (e.g. dissolution) can be used instead if
statistical correlation to in vivo data has been established. Example: dermato-PK for topical
drugs for local effect.

Plasma drug concentration

Most common method for measuring systemic bioavailability.
Time for peak plasma concentration (Tmax): relates the rate constant for drug absorption
and elimination. Absorption depends on the dosage form and formula, while elimination is
only drug dependent.
Peak plasma concentration (Cmax): Cmax at Tmax relates to the intensity of
pharmacological response. Ideally Cmax should be within the therapeutic window.
AUC vs time: relates the amount or extent of systemic drug absorption. AUC is calculated
using the trapezoidal rule, expressed as mg.hr/ml

Urinary drug excretion

Accurate method if the active moiety is excreted unchanged in ↑ quantities in urine.
Cumulative amount of active drug excreted in urine is related to extent of systemic drug
absorption. Rate of drug excretion is related to rate of systemic absorption. Time for
complete excretion relates to the total time for complete systemic absorption and excretion.

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Relative and absolute bioavailability
Relative bioavailability: systemic availability of the drug from a dosage form as compared to
reference standard given by the same route. It is a ratio of the AUCs (maximum is 1 or 100%).
Very important for generic bioequivalence studies.
Absolute bioavailability (F): fraction of drug that is systemically absorbed. It’s the ratio of
AUC for oral dosage form / AUC for IV. A parenteral IV drug solution has F = 1.

A –Relative bioavailability = comparative bioavailability = Bioequivalents.

Compare with Reference standard
[ Auc ] product / dose
% R.B =  100
[ Auc ]ref .st. / dose
N.B: we divide by dose in case of 2 product e\ different doses.

In urine data

[ Du] product / dose

% R.B =  100
[ Du] ref .st. / dose

Reference Standard specifications:

1. Should contain active drug in its most bioavilable formulation (i.e. solution or suspension).
2. Should be administered by same route as compared formulation.
3. When solution or suspension of drug is not available (or very bitter most safe and effective
product in market is taken as ref. Stand (usually the Innovator).
4. Should be accepted by medical profession.
5. It is usually the drug product of the original manufactures. i.e. innovator product.

N.B: Relative bioavailability can’t determine the fraction of drug absorbed (F) but it gives
indication about rate and extent of drug absorption.

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B – Absolute bioavailability: compare with I.V dose.
[ Auc ] product / dose
A.B =
[ Auc ]I .V / dose

[ Du ] product / dose
= [ Du] ref .st. / dose
Absolute bioavailability gives an indication about:
1 – Rate and extent of drug absorption.
2 – 1st pass effect as well as fraction of drug absorbed “F” (or fraction that is
BIOAVAILABLE).
I.V drugs F = 1 (except for prodrugs as it depend on its conversion into active form
by enzyme system).********
Oral drugs F ≤ 1 [one only in case of H2O]

Assessment (evaluation) of 1st pass effect:

I.V dose = Cl  {AUC} I.V
F * Oral dose = Cl  {AUC} oral
DoseI .V  [ AUC ]oral
F=
Doseoral  [ AUC ]I .V

Bioequivalence for solid dosage forms

Design of bioequivalence studies

Guidance provided by Division of Bioequivalence, Office of Generic Drugs, FDA. All studies
are done with healthy subjects.
Fasting study: blood samples are taken at zero time, and appropriate intervals to obtain
adequate description of concentration vs. time profile.
Food intervention study: required if bioavailability is known to be affected by food. Give
products immediately after a standard high fat content breakfast.

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Multiple dose steady-state study: required for extended release products in addition to
single-dose fasting and food intervention study. Measure three consecutive days of trough
concentrations (Cmin) to ascertain steady state. Last morning dose is given after overnight
fast, continue fasting for 2 hours. Take blood samples.
In vitro bioequivalence waiver: a comparative in vitro dissolution may be used instead for
some immediate release oral dosage forms. No bioequivalence study is required for certain
solution products (oral, parenteral, ophthalmic).

PK data evaluation
Single dose studies: calculate AUC to last quantifiable concentration, AUC to infinity, Tmax,
Cmax, elimination rate constant (K), elimination half life (t1/2).
Multiple dos studies: steady state AUC, AUC to last quantifiable concentration, Tmax,
Cmax, Cmin, % fluctuation (Cmax-Cmin / Cmin).

Statistical data evaluation

Drug considered bioequivalent if difference from reference is < -20% or +25%. ANOVA is
done on log transformed AUC and Cmax data. The 90% confidence interavals of the means of
AUC and Cmax should be 80-125% of the reference product.

Drug production selection

Generic drug substitution

It’s dispensing generic drug in place the prescribed product. The substituted drug has to be a
therapeutic equivalent.
Prescribability: current basis for FDA approval of therapeutic equivalent generic product.
It’s measurement of average bioequivalence where test and reference population means are
statistically the same.
Switchability: assures that the substituted product produces the same response in the
individual patient. It’s the measurement of the individual bioequivalence including intra-
subject variability and subject-by-formulation effects.

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Therapeutic substitution
The process of dispensing a therapeutic alternative. For example: dispensing amoxicillin for
ampicillin. The substituted drug is usually in the same therapeutic class (e.g. calcium channel
blockers) and is expected to have a similar clinical profile.

Formulary issues
A formulary is a list of drugs. Positive formulary: lists all drugs that may be substituted.
Negative formulary: lists drugs which can’t be substituted. Restrictive formulary: lists only
drugs that may be reimbursed without justification by the prescriber. States provide guidance
for drug product selection through formulary.
FDA annually publishes Approved Drug Products with Therapeutic Equivalence Evaluations
(the “Orange Book”). It is also published in the USP/DI Volume III.
Orange Book Codes: A Rated: drug products that are considered therapeutically equivalent.
B Rated: drug products that are not considered therapeutically equivalent. AB Rated:
products meeting bioequivalence requirements.

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